Over the past four decades the incidence of melanoma has been increasing at a higher rate than any other type of cancer. It is now theorized that one in ninety American Caucasians will develop malignant melanoma in their lifetime. While an increasing proportion of melanomas are diagnosed sufficiently early to respond to surgical treatment and achieve a greater than 90% ten-year survival rate, it is estimated that nearly 7,000 individuals suffering from metastatic melanoma will die in the United States each year.
For patients afflicted with a metastatic melanoma not amenable to surgical extirpation, treatment options are limited. 5-(3,3-Dimethyl-1-triazenyl)-1-H-imidazole-4-carboxamide (dacarbazine, DTIC) is the most efficacious single chemotherapeutic agent for melanoma having an overall response rate of 24%. But the duration of response to DTIC is generally quite poor. Combination therapy with other synthetic and recombinant agents, including N,N′-bis(2-chloroethyl)-N-nitrosurea (carmustine, BCNU), cisplatin, tamoxifen, interferon-alpha (INF-α), and interleukin-2 (IL-2), has a higher response rate (e.g., 30–50%) in some trials, but a durable complete response rate is uncommon and toxicity is increased. Sequential chemotherapy also has promise, but current treatment options for individuals suffering from metastatic melanoma are unsatisfactory.
Various drugs derived from natural products, such as adriamycin (doxorubicin), bleomycin, etoposide, and vincristine, and their derivatives, have been tested for efficacy against melanoma either as single agents or in combination therapy. However, similar to the synthetic and recombinant compounds, these compounds exhibit low response rates, transient complete responses, and high toxicities.
Nonetheless, as demonstrated by known and presently used cancer chemotherapeutic agents, plant-derived natural products are a proven source of effective drugs. Two such useful natural product drugs are paclitaxel (taxol) and camptothecin. Paclitaxel, originally derived from the bark of the Pacific yew tree Taxus brevifolia Nutt. (Taxaceae), currently is used for the treatment of refractory or residual ovarian cancer. More recently, clinical trials have investigated the possible role of paclitaxel in the treatment of metastatic melanoma. As a single agent, taxol displays activity comparable to cisplatin and IL-2. Taxol functions by a unique mode of action, and promotes the polymerization of tubulin. Thus, the antitumor response mediated by taxol is due to its antimitotic activity.
The second drug of prominence, camptothecin, was isolated from the stem bark of a Chinese tree, Camptotheca acuminata Decaisne (Nyssaceae). Camptothecin also functions by a novel mechanism of action, i.e., the inhibition of topoisomerase I. Phase II trials of a water-soluble camptothecin prodrug analog, irinotican (CPT-11), have been completed in Japan against a variety of tumors with response rates ranging from 0% (lymphoma) to 50% (small cell lung). Topotecan, another water-soluble camptothecin analog, currently is undergoing Phase II clinical trials in the United States.
In addition, studies have shown that betulinic acid, and betulinic acid derivatives, can inhibit other types of cancer cells, such as neuroblastoma, in addition to melanoma. For example, Das Gupta et al. U.S. Pat. No. 5,658,947 discloses that betulinic acid is useful for the selective control or treatment of human melanoma, and Pezzuto et al. U.S. Pat. No. 5,962,527 discloses the selective activity of derivatives of betulinic acid against melanoma cells.
However, a disadvantage associated with the use of betulinic acid or a betulinic acid derivative in the treatment of a cancer is the problem encountered in formulating these active drugs and in providing suitable dosage forms for the treatment of various cancers. The present application is directed to overcoming this disadvantage and providing useful prodrugs of betulinic acid and derivatives thereof that are easy to formulate into a variety of dosage forms and that release betulinic acid or the derivative thereof in vivo.